Ethosuximide and Phenobarbital: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Phenobarbital
Ethosuximide
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Decreased ethosuximide serum concentrations
Interaction Deep Dive
In a controlled study, patients taking either carbamazepine, phenytoin, or phenobarbital had a significantly decreased half-life and higher oral clearance of ethosuximide compared to healthy volunteers on no chronic medications1. Conversely, other reports state that phenytoin, phenobarbital, primidone and carbamazepine do not appear to alter the kinetics of ethosuximide 3.
Why it happens (mechanism)
Phenobarbital induction of cytochrome P450 enzymes
Literature reports
2 reports — tap to read
a) In a study of 22 volunteers, the effects of chronic epileptic medication on the pharmacokinetics of ethosuximide were evaluated. The study consisted of 10 patients with epilepsy undergoing chronic treatment with carbamazepine, phenytoin, or phenobarbital, and 12 healthy control subjects taking no chronic medications. Each subject received a single 500 mg oral dose of ethosuximide after an overnight fast. Patients on chronic epileptic therapy had a decreased mean ethosuximide half-life of 29.0 hours +/- 7.8 hours compared to 53.7 hours +/- 14.3 hours for control subjects. Patients on chronic epileptic therapy also had higher oral clearance values and slightly decreased apparent volume of distribution values compared to control patients. The authors postulate that the mechanism of action was due to antiepileptic medication induction of cytochrome CYP3A 1.
b) An absence seizure patient experienced an increase in seizure frequency when ethosuximide was added to chronic phenobarbital therapy 2.
Common questions
Can I take Ethosuximide and Phenobarbital together?
Decreased ethosuximide serum concentrations Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ethosuximide and Phenobarbital interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Ethosuximide or Phenobarbital need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (3)
- Giaccone M, Bartoli A, Gatti G, et al: Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1996; 41:575-579. DOI
- Todorov AB, Lenn NJ, & Gabor AJ: Exacerbation of generalized nonconvulsive seizures with ethosuximide therapy. Arch Neurol 1978; 35:389-391. DOI
- Smith GA, McKauge L, Dubetz D, et al: Factors influencing plasma concentrations of ethosuximide. Clin Pharmacokinet 1979; 4:38-52. PubMed
Keep reading about Phenobarbital
Keep reading about Ethosuximide
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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